JP6847200B2 - Automatic analyzer - Google Patents

Description

The present invention relates to an automatic analyzer provided with a sample dispensing unit that sucks and discharges a sample such as blood or urine, and particularly relates to an automatic analyzer having a function of detecting that air bubbles have been mixed into the probe during liquid suction. ..

In automatic analyzers such as biochemical analyzers and immunoanalyzers, a sample dispensing unit that dispenses a part of a sample such as serum or plasma collected from a patient into a container is required for sample analysis. It is provided with a reagent dispensing unit that sucks a part of the reagent and discharges it into the container.

Generally, a sample dispensing unit or a reagent dispensing probe is provided with a probe, a syringe connected to the probe, and a mechanism for moving the probe to a predetermined position, and drives the syringe with the tip of the probe inserted in the liquid. This sucks a predetermined amount of liquid into the probe. After that, the probe is moved onto the container and the syringe is driven to discharge the sucked liquid. In some cases, a disposable tip is attached to the tip of the probe to suck and discharge the liquid.

By the way, air bubbles may be unintentionally mixed in during liquid handling. Under such circumstances, if a predetermined amount of liquid cannot be sucked due to suction of air bubbles together with the liquid during liquid suction, an analysis error will occur and re-examination will be required, resulting in a decrease in analysis throughput. This will result in loss of specimens and reagents.

As a means for solving such a problem, for example, Patent Document 1 uses the integrated pressure value in a specific section and the average pressure difference between the steady discharge and the end of discharge as an index for the pressure fluctuation at the time of sample discharge. Is configured to detect a sample dispensing abnormality by comparing with a preset threshold value.

Special Table No. 11-501399

The method of paying attention to the pressure integrated value and the pressure change rate in a specific section of the pressure in the dispensing flow path at the time of sample discharge as in Patent Document 1 can detect an abnormality when a relatively large difference is observed in the pressure waveform. However, there is a problem that an abnormality cannot be detected when the sample dispensing amount is small and no large difference is observed in the pressure waveform between the normal state and the abnormal state.

In view of the above problems, it is an object of the present invention to provide an automatic analyzer capable of detecting a dispensing abnormality with high sensitivity regardless of the degree of abnormality even when the liquid dispensing amount is small.

The configuration of the device for solving the above problem is as follows.

That is, a probe that performs dispensing of a liquid including a suction step and a discharge step, a syringe that generates a pressure fluctuation for dispensing the liquid with the probe, and a flow path that connects the probe and the syringe. , A pressure sensor that measures the pressure fluctuation in the flow path during liquid dispensing, a storage unit that stores the time-series pressure fluctuation when the reference fluid is discharged as a reference discharge pressure waveform, and determination of the reference discharge pressure waveform. includes the value of the difference or the ratio of the pressure waveform at the time of discharging the liquid of interest, the relationship between the predetermined range, the determination unit that there is an abnormality in the suction step of the liquid body, the storage unit, the The relationship between the timing outside the predetermined range and the amount of air mixed in the liquid is stored for each preset dispensing amount, and the determination unit estimates the amount of air mixed in from the timing outside the predetermined range. It is characterized by having a function.

According to the present invention, abnormalities such as bubble suction can be detected regardless of the degree of abnormality even when the sample dispensing amount is small and no large difference is observed between the normal waveform and the abnormal waveform, and the sample dispensing can be performed. It has the effect of increasing the reliability of the analysis results of the automatic analyzer equipped with the unit.

It is a schematic block diagram of the automatic analyzer which concerns on this invention. It is a schematic block diagram of the sample dispensing unit of the automatic analyzer which concerns on this invention. It is a figure which shows the pressure fluctuation in a dispensing flow path at the time of liquid suction and the time of discharge. It is a figure which shows the state of the fluid movement in a chip when sucking and discharging air bubbles together with a liquid sample. It is a figure which shows the processing flow of the dispensing abnormality detection when a liquid sample is used as a reference fluid. It is a figure which shows the processing flow of the dispensing abnormality detection when air is used as a reference fluid. It is a figure which shows the correlation of the timing which the discharge pressure at the time of bubble suction deviates from a reference discharge pressure, and the ratio of the bubble suction amount. It is a figure which shows the time series data of the pressure in a flow path at the time of liquid discharge. It is a figure which shows the result of having converted the time-series data of the pressure in a flow path at the time of liquid discharge into the time-series data of the pressure difference with the reference discharge pressure waveform (using a liquid sample as a reference fluid). It is a figure which shows the result of having converted the time-series data of the pressure in a flow path at the time of liquid discharge into the time-series data of the pressure difference with the reference discharge pressure waveform (using air as a reference fluid). It is a figure which shows the timing suitable for the measurement of a reference discharge pressure. It is a figure which shows the arrangement of the container which holds a reference liquid.

Hereinafter, examples of the invention will be described with reference to the drawings.

FIG. 1 is a schematic configuration diagram of an automatic analyzer 101 to which the dispensing abnormality detection technique of this embodiment is applied.

In FIG. 1, the automatic analyzer 101 includes a rack transfer line 103 for transporting a rack 102, a reagent cooling unit 104, an incubator disk (reaction disk) 105, a sample dispensing mechanism (sample dispensing mechanism) 106, and a reagent. It includes a dispensing mechanism 107, a consumables transport unit 108, and a detection unit 109. Each of the above components may be called a unit.

The rack 102 stores a plurality of sample containers (sample containers) 110 for storing biological samples (samples) such as blood and urine, and transports the sample containers 110 on the rack transfer line 103 in a state of being stored. Will be done.

The reagent cold storage unit 104 stores and cools a plurality of reagent containers 111, which are reagent container storage units and contain various reagents used for analysis of a sample (sample). At least a part of the upper surface of the reagent cooling unit 104 is covered with the reagent disc cover 112.

The incubator disk 105 has a reaction vessel arrangement unit 114 in which a plurality of reaction vessels 113 for reacting a sample and a reagent are arranged, and a temperature adjusting mechanism for adjusting the temperature of the reaction vessel 113 to a desired temperature.

The sample dispensing mechanism 106 has a rotation drive mechanism and a vertical drive mechanism, and it is possible to dispense a sample from the sample container 110 to the reaction container 113 housed in the incubator disk 105 by these drive mechanisms. Further, the reagent dispensing mechanism 107 also has a rotation drive mechanism and a vertical drive mechanism, and the reagent is dispensed from the reagent container 111 to the reaction vessel 113 housed in the incubator disc 105 by these drive mechanisms. The detection unit 109 includes a photomultiplier tube, a light source lamp, a spectroscope, and a photodiode, has a function of adjusting the temperature of these, and analyzes the reaction solution.

The consumables transport unit 108 temporarily holds a storage container holding unit 117 for holding a consumables storage container 116 for storing a plurality of consumables used for sample analysis such as a reaction container and a dispensing chip, and these consumables. It is composed of a spare storage unit 118 and a transport mechanism 119 that grips and transports consumables, and the transport mechanism 119 transports the consumable storage container 116, the reaction container 113 on the spare storage unit 118, and the dispensing chip 115 to a predetermined position. Has the function of

The consumables container 116, also called a magazine, is provided with a plurality of recesses or holes on the upper surface, and the consumables are supplied to the operator in a state where the consumables are stored one by one in the recesses or holes. Since these consumables are disposable, the operator must periodically supply the consumable container 116 to the automated analyzer and eject the empty consumable container 116 from which all consumables have been consumed.

The transport mechanism 119 is movably provided on rails provided in the X-axis, Y-axis, and Z-axis directions (not shown), and incubates the reaction vessel 113 stored in the consumable storage container 116 and the spare storage unit 118. It is conveyed to the disk 105 or the dispensing tip 115 is conveyed to the tip mounting position 120. Also, the used reaction vessel 118 on the incubator disc 105 is discarded in the waste hole 121. Further, the transport mechanism 119 transports the unused reaction container 113 and the dispensing tip 115 on the consumable storage container 116 to the spare storage section 110, and the reaction vessel 113 and the dispensing tip 115 on the spare storage container 110 are respectively incubators. It is conveyed to the disk 107 or the chip mounting position 120. Therefore, the transport mechanism 119 has an arm structure for gripping the reaction vessel and the dispensing tip.

The spare storage unit 118 holds the reaction container 113 and the dispensing tip 115 in the same manner as the consumable storage container 116. The transport mechanism 119 installs the reaction vessel 113 and the dispensing tip 115 in the spare storage section 118, and supplies the reaction vessel 113 and the dispensing tip 115 held on the spare storage section 118 to the incubator disk 105 and the dispensing tip. It can be transferred to position 120.

The storage container holding unit 117 can be pulled out toward the front, back, or side of the device independently of the other mechanical parts, and the consumables storage container 116 by the user is in a state where the other mechanism does not access the consumables storage container 116. Can be exchanged. The storage container holding portion 117 may be provided with a door or a lid, and the operator may be allowed to access by opening and closing the door or the lid. Further, the storage container holding portion 117 is provided with a lock mechanism, and it is possible to prevent the mechanism such as the transport mechanism 119 from being pulled out when the consumable storage container 116 is accessed by the lock mechanism. Further, the storage container holding unit 117 has a sensor for detecting whether or not the consumables storage container 116 is installed, and detects whether or not the consumables storage container 116 has been replaced when the storage container holding unit 117 is pulled out. can do.

Among the automatic analyzer 101, the rack transport line 102, the reagent container disc 104, the incubator disc 105, the sample dispensing mechanism 106, the reagent dispensing mechanism 107, the consumables transport unit 108, and the detection unit 109, which have been described above, Etc. are referred to as an analysis operation unit.

Further, the automatic analyzer 101 includes, in addition to the analysis operation unit described above, a control device (control unit) 122 that controls the operation of the entire automatic analyzer 101, and an operation unit 123. The control unit 122 is composed of, for example, a hardware board, and is connected to a control device 124 such as a computer or a storage device 125 such as a hard disk. The operation unit 123 is composed of, for example, a display unit which is a display and an input device such as a mouse and a keyboard. The storage device 125 stores, for example, a temperature range corresponding to each unit. The control unit 122 and the control device 124 may be configured as hardware by a dedicated circuit board, or may be configured by software executed by a computer connected to the automatic analyzer 101. When configured by hardware, it can be realized by integrating a plurality of arithmetic units that execute processing on a wiring board or in a semiconductor chip or a package. When it is configured by software, it can be realized by mounting a high-speed general-purpose CPU on a computer and executing a program that executes desired arithmetic processing. It is also possible to upgrade existing equipment with the recording medium on which this program is recorded. Further, these devices, circuits, and computers are connected by a wired or wireless network, and data is appropriately transmitted and received.

<Sample dispensing unit>
FIG. 2 is a schematic view of a sample dispensing unit according to the present invention.

The sample probe 202 to which the freely removable tip 201 is attached is connected to the syringe 204 via the flow path 203, and the inside thereof is filled with a liquid. The syringe 204 is composed of a cylinder 204a and a plunger 204b, and a syringe driving means 205 is connected to the plunger 204b. By driving the plunger 204b up and down with respect to the cylinder 204a by the syringe driving means 205, the sample is sucked and discharged. A motor is connected to the sample probe 202 as a sample probe driving means 206, whereby the sample probe 202 can be moved in the horizontal direction and the horizontal direction and positioned at a predetermined position. The syringe driving means 205 and the sample probe driving means 206 are controlled by the control unit 207.

When the sample 209 in the container 208 is sucked, air (segmented air) is sucked into the chip 201 prior to the suction operation so that the liquid filled in the sample probe 202 and the sample 209 do not mix with each other. .. After that, the sample probe driving means 206 lowers the sample probe 202 until the tip of the chip 201 reaches the sample 209 liquid, and further performs a suction operation. When the sample suction operation is completed, the sample probe 202 moves to the sample discharge position, and the syringe 204 performs the sample discharge operation.

After discharging, the sample probe 202 can be washed by discharging the washing water 212 in the water supply tank 211 at a high pressure by the water supply pump 210. The flow path to the water supply tank is opened and closed by the solenoid valve 213. The solenoid valve 213 is controlled by the control unit 207.

The pressure sensor 214 for measuring the pressure in the flow path 203 is connected to the flow path system including the sample probe 202, the flow path 203, and the syringe 204 via the branch block 215. Here, since the pressure sensor 214 measures the pressure fluctuations of the sample probe 202 and the opening of the tip 201 with high sensitivity, it is desirable to install the pressure sensor 214 on the sample probe 202 side as much as possible. The output value of the pressure sensor 214 is amplified by the signal amplifier 215 and converted into a digital signal by the A / D converter 216. The digitally converted signal is sent to the determination unit 217, and it is determined whether or not the sample has been normally sucked by the method described below.

<Pressure waveform in sample dispensing unit>
FIG. 3 shows a pressure waveform obtained when a liquid is dispensed by setting the dispensing amount to 30 μL in a sample dispensing unit equipped with a pressure sensor. The horizontal axis represents time, and the vertical axis represents the output value of the pressure sensor. Here, the liquid is assumed to be a sample, a reagent, washing water, or the like, and is not particularly limited.

FIGS. 3A and 3B show pressure waveforms at the time of suction and discharge of the liquid, respectively. The solid line L1 is the discharge pressure when the sample is normally sucked and discharged, and the broken lines L2 and L3 are the discharge pressures when bubbles are sucked together with the liquid. The broken line L2 shows the case where nearly half of the set suction amount is sucked, and the broken line L3 shows the case where nearly 90% of the bubbles are sucked.

As is clear from this figure, the pressure at the time of suction is less likely to show a large difference in the waveform between the normal time and the abnormal time than the pressure at the time of discharge. That is, the pressure waveform at the time of suction almost overlaps with the normal waveform (solid line L1) when about half of the bubbles are sucked (dashed line L2), and only when nearly 90% of the bubbles are sucked (dashed line L3) at normal time. On the other hand, it gives a certain difference.

On the other hand, it can be seen that there is a large difference in the waveform of the pressure at the time of discharge between the normal time and the abnormal time. Immediately after the start of discharge, the normal waveform and the abnormal waveform overlap, but a divergence occurs between them from a certain timing (arrow A in FIG. 3 (b)). Then, just before the end of discharge, they overlap again (arrow B in FIG. 3B). Further, the timing at which the above-mentioned deviation occurs depends on the amount of bubble suction. This is because the above divergence occurs at the timing of shifting from the liquid discharge process to the bubble discharge process. 4 (a) and 4 (b) show the fluid movement in the chip 403 when the bubble 402 is sucked or discharged together with the liquid sample 401, respectively. As shown in FIG. 4A, the liquid sample 401 is initially sucked, and bubble suction starts at the timing when the tip tip separates from the liquid surface as the liquid level drops. The bubbles 402 mixed in the chip 403 float on the surface of the sucked liquid sample 401. When the liquid sample 401 is discharged in this state, the liquid sample 401 is first discharged, and then the bubble 402 is discharged (FIG. 4 (b)). The dissociation begins at the timing of switching from the liquid discharge process to the bubble discharge process. Therefore, when the amount of suction of bubbles is large and the amount of suction of liquid is small, the timing of switching from liquid discharge to bubble discharge is earlier. That is, it is possible to determine how much the bubble 402 is sucked by paying attention to the timing at which the dissociation starts.

According to the present invention, in the conventional method described in Patent Document 1 (a method focusing on the pressure integral value in a specific section), it is not possible to discriminate between a normal time and an abnormal time unless the integration section is set appropriately. It was. For example, if the integration section is set at a relatively early stage immediately after the start of discharge, an abnormality can be detected when nearly 90% of the bubbles are sucked (broken line L3), but when about half of the bubbles are sucked (broken line L2). However, according to the method of this embodiment, it is possible to detect bubbles with high accuracy and even the amount of sucked bubbles by a simple method.

<Algorithm for detecting dispensing abnormality (when the reference pressure waveform is taken with liquid)>
Next, the processing flow of dispensing abnormality detection according to the present invention will be described. FIG. 5 is a determination algorithm when the pressure waveform when the reference fluid is discharged is used as the reference pressure waveform.

The present invention detects an abnormality during liquid suction by using the pressure in the dispensing flow path during sample discharge. First, the liquid is sucked into the sample probe (S51). Next, at the same time that the probe 202 discharges the liquid 209, the sampling unit 219 collects the output value of the pressure sensor 214 in time series (S52). The collected pressure data is converted into time-series data of the pressure difference or pressure ratio from the reference discharge pressure waveform (S53). Here, it is assumed that the reference discharge pressure waveform is defined in advance for each set dispensing amount and stored in the storage unit 220.

The comparison unit 221 sequentially monitors whether the pressure difference or the pressure ratio from the reference discharge pressure waveform is out of the normal range (S54, S55). Then, if the sample is not out of the normal range even once until the discharge is completed, the sample suction is determined to be normal (S56). On the other hand, if the sample is out of the normal range even once, the sample suction is determined to be abnormal (S57). Here, it is assumed that the normal range referred to at the time of determination is defined in advance for each set dispensing amount and stored in the storage unit 220. In the present invention, the case where the suction is out of the normal range even once is determined as a suction abnormality, but the case where the suction is out of the range a plurality of times or more may be determined as an abnormality, and a plurality of cases may be determined within a predetermined time. It is also possible to determine that it is abnormal when it goes out of the range of times.

Further, the comparison unit 221 can estimate the degree of abnormality at the time of liquid suction, that is, how much air bubbles are mixed, based on the timing when the pressure difference from the reference discharge pressure waveform or the pressure ratio is out of the normal range. is there. For this estimation, a correlation curve showing the correlation between the timing outside the normal range (timing when an abnormality is detected) and the degree of abnormality is used. It is assumed that this correlation curve is defined in advance for each set dispensing amount and stored in the storage unit 220.

Further, the comparison unit 221 may estimate the cause of the abnormality based on the estimated degree of the abnormality. For example, it is presumed that the cause of the determination of complete air suction is not the bubbles on the liquid surface but the abnormality of the dispensing system such as the failure of the syringe or the clogging of the sample probe.

<Algorithm for detecting dispensing abnormality (when the reference pressure waveform is taken with air)>
FIG. 6 shows a processing flow for detecting dispensing abnormality when air is used instead of liquid as the reference fluid. Here, the steps (S61 to S63) for converting the discharge pressure waveform at the time of liquid dispensing to be determined into the pressure difference or pressure ratio from the reference discharge pressure waveform are the same as those in the flowchart of FIG. Omit.

Here, since the air discharge pressure at the time of air suction is used as the reference discharge pressure waveform, when the pressure waveform at the time of liquid discharge of the judgment target completely matches the reference pressure waveform, the liquid suction to be judged is air suction. judge. That is, the comparison unit 221 sequentially monitors the pressure difference or pressure ratio from the reference pressure waveform, and if they never deviate from a certain determination range in consideration of the variation in the reference pressure, the sample suction is air-sucked. (S66). Conversely, it is possible to say that a range other than the above-mentioned "constant determination range" is a "normal range", and if it continuously deviates from the normal range during the discharge process, it is determined that air suction is performed. It is also possible that there is.

On the other hand, if the syringe 204 is discharged from the determination range (that is, from a state that does not deviate from the "normal range") and then falls within the determination range again at the same time, the sample suction is determined to be normal (S68). .. Then, if neither of the above applies, it is determined that some air bubbles have been sucked (S69). Here, it is assumed that the reference pressure waveform and the determination range to be referred to at the time of determination are defined in advance for each set dispensing amount and stored in the storage unit 220.

Further, the comparison unit 221 estimates the degree of abnormality based on the timing from when the difference or ratio between the pressure waveform at the time of discharging the liquid to be determined and the reference pressure waveform once deviates from the determination range and then falls within the determination range again. You may. In this case, as the degree of abnormality, it is possible to determine how much air is mixed in the pipette when the liquid is sucked.

Further, the cause of the abnormality may be estimated based on the estimated degree of abnormality. For this estimation, a correlation curve showing the relationship between the time from when the range is once out of the range to when it is within the range again and the degree of abnormality is used. It is assumed that this correlation curve is defined in advance for each set dispensing amount and stored in the storage unit 220.

As described above, the sample suction abnormality can be detected regardless of whether liquid or air is used as the reference fluid.

<How to create a reference pressure waveform>
Next, the details of the method of acquiring the reference discharge pressure waveform, the method of setting the pressure range to be referred to when determining normality / abnormality, and the method of creating the correlation curve will be described.

The reference discharge pressure waveform is the discharge pressure acquired when the reference fluid is normally sucked and discharged. The reference fluid is one whose viscosity is within the viscosity range of the sample handled by the automatic analyzer and does not contain solid foreign matter or the like. For example, in the case of an automatic analyzer, a liquid sample having a viscosity equivalent to that of human serum and containing no clot or the like corresponds to it. Controlled serum and purified water can be considered as samples that satisfy this requirement. As described above, not only the liquid but also the reference fluid may be used as air for air suction. With air suction, it is not necessary to prepare a reference fluid, so the burden of acquiring the reference discharge pressure waveform can be reduced.

On the other hand, normal suction and discharge means that the dispensing operation is completed without any abnormality such as clogging of the sample probe under the condition that there are no bubbles on the liquid surface. Further, as a premise, it is assumed that the variation of each component of the sample dispensing unit, such as the variation of the inner diameter of the sample probe and the variation of the pressure sensor sensitivity, is within the predetermined tolerance.

After satisfying the above conditions, the discharge pressure waveform is measured a plurality of times with respect to the reference fluid, and the average waveform is defined as the reference discharge pressure waveform. Here, by performing as many measurements as possible and accurately defining the reference discharge pressure waveform, the accuracy of determining normality and abnormality can be improved. Details regarding the acquisition of the reference discharge pressure waveform will be described later.

The pressure range to be referred to when determining normality or abnormality is defined based on the variation of the reference discharge pressure waveform. Here, if the range is set narrow, the sensitivity of abnormality detection is improved, but on the other hand, the probability of false detection is also increased. Therefore, it is important to set the above range while maintaining a good balance between them.

In addition, there is a certain correlation between the abnormality detection timing (timing when it is determined that air bubbles are mixed) and the degree of abnormality. FIG. 7 shows an example of the correlation curve. If a correlation curve relating to the abnormality detection timing and the degree of abnormality is set in advance, when an abnormality actually occurs, the degree of abnormality can be estimated from the timing at which the abnormality occurs. Here, by making as many measurements as possible and defining this correlation curve accurately, the estimation accuracy can be improved.

The reference discharge pressure waveform, normal range, and correlation curve obtained by the above method need to be prepared according to all the set dispensing amounts applied by the automatic analyzer to be used. This is because the driving conditions of the dispensing syringe and the sample probe differ depending on the dispensing amount, and the discharge pressure waveform also changes accordingly. However, in general automatic analyzers, the minimum and maximum dispensing amount and dispensing resolution are determined by the specifications, and since the types of dispensing amount are finite, there are as many reference discharge pressure waveforms and normal ranges as there are. , It suffices to have a set of correlation curves.

What has been described so far about the abnormality detecting means in the present invention will be described by showing the pressure waveform actually obtained.

<Time series data of pressure>
FIG. 8 shows an example of time-series data of the pressure in the flow path collected by the pressure sensor 214 when the liquid to be determined is discharged.

The horizontal axis represents time, and the vertical axis represents the output value of the pressure sensor. Further, the solid line L1 is the pressure in the flow path (reference discharge pressure waveform) at the time of discharge when the liquid is normally dispensed as the reference fluid. On the other hand, the broken lines L2 and L3 are the pressures in the flow path at the time of discharge when the bubbles are sucked together with the liquid. The broken line L2 shows the case where nearly half of the set suction amount is sucked, and the broken line L3 shows the case where nearly 90% of the bubbles are sucked. As shown in FIG. 8, when air bubbles are sucked during suction, the pressure in the flow path drops sharply from a certain timing of the sample discharge section and begins to deviate from the reference discharge pressure waveform (arrows A and B in the figure). The deviation from the reference discharge pressure waveform can be directly expressed by converting the pressure in the flow path at the time of liquid discharge into a pressure difference from the reference discharge pressure waveform.

<Time series data of pressure difference>
FIG. 9 shows a pressure difference between the pressure in the flow path during liquid discharge (curves L2 and L3 in FIG. 8) and the reference discharge pressure waveform (curve L1 in FIG. 8).

The converted values are represented by dashed lines L2'and L3', respectively. The horizontal axis is time, and the vertical axis is the relative pressure value with respect to the reference discharge pressure waveform. When the pressure in the flow path at the time of discharge is higher than the reference discharge pressure waveform, it takes a positive value, and when it is lower, it takes a negative value. Here, if this relative pressure deviates from the normal range even once at a certain timing in the liquid discharge section, it is determined as abnormal suction. In FIG. 9, the minimum value and the maximum value of this normal range are shown by Pmin and Pmax, respectively. As described above, in order to prevent false detection, it is desirable to set the normal range as wide as possible in consideration of the variation of the reference discharge pressure waveform.

The broken lines L2'and L3'are out of the normal range at the timings of T1 and T2, respectively. Therefore, in both cases, it is determined that an abnormality (bubble suction) has occurred in the liquid suction. Further, by using a correlation curve showing the correlation between the timing and the bubble suction amount, which is defined in advance for each preset dispensing amount, the degree of abnormality (bubble suction) from the timing when the abnormality is detected (T1, T2). Amount) can be estimated to some extent.

Next, FIG. 10 shows time-series data of the pressure difference in the flow path (solid line L1 and broken line L2 in FIG. 8) and the reference discharge pressure waveform when the reference fluid is air.

The converted curve is represented by a solid line L1'and a broken line L2', respectively. The horizontal axis is time, and the vertical axis is the relative pressure value with respect to the reference discharge pressure waveform. When the pressure in the flow path at the time of discharge is higher than the reference discharge pressure waveform, it takes a positive value, and when it is lower, it takes a negative value. Here, if this relative pressure never deviates from the set range in the sample discharge section, it is determined as air suction. On the other hand, if the syringe is out of the set range and then falls within the range again at the same time as the syringe discharge operation is completed, the sample suction is determined to be normal. Then, if neither of the above applies, it is determined that some air bubbles have been sucked. In FIG. 10, the minimum value and the maximum value of the setting range are shown by Pmin and Pmax, respectively. As described above, in order to prevent false detection, it is desirable to set this setting range as wide as possible in consideration of the variation of the reference discharge pressure waveform.

The solid line L1'and the broken line L2'are out of the set range, respectively, and then fall within the set range again at the timings of T1 and T2, respectively. Here, since T1 is at the same time as the discharge operation completion timing of the syringe, it is determined that the liquid suction has been normally performed on the solid line L1'. On the other hand, since the broken line L2'is within the set range at a timing earlier than the completion of the discharge operation, it is determined that an abnormality (bubble suction) has occurred during liquid suction.

Further, a correlation curve showing the correlation between the time until the sample suction abnormality is detected and the bubble suction amount is stored for each set dispensing amount in advance, and the degree of abnormality (bubble suction) is stored from the timing (T2) when the sample suction abnormality is detected. Amount) can be estimated to some extent.

FIG. 11 shows the timing of obtaining a reference pressure waveform that is effective for removing factors that affect the pressure waveform. The timing shown in FIG. 11 is an example, and it is not always necessary to carry out the timing at the listed timings, and it is not necessary to carry out even when the influence of the influential factors is small.

Factors that may affect the pressure waveform include (1) individual differences in hardware, (2) changes in the environment where the equipment is installed, such as atmospheric pressure, and (3) differences in inspection dates.

First, since the influence of individual hardware differences can be eliminated by providing a reference discharge pressure waveform for each device, the reference discharge pressure waveform may be acquired at the time of shipment of the device. Examples of the reference fluid to be used include purified water and air (air suction).

The effects of changes in the environment where the equipment is installed, such as atmospheric pressure, can be eliminated by acquiring the reference discharge pressure waveform when the equipment is installed in the inspection room. It also has the advantage of eliminating the effects of individual hardware differences. Here, examples of the reference fluid include purified water and air (air suction).

In order to eliminate the influence of the difference in the test date, the pressure may be obtained when the assay calibration is performed. Here, the assay calibration is a step for periodically correcting the calibration curve used when converting the measurement signal obtained by the analysis unit of the apparatus into the concentration of the object to be measured, and all the inspection items. Is carried out against. The reference fluid in this case is the calibrator. Obtaining a reference discharge pressure waveform in this process has several advantages. The first is that the assay calibration is performed relatively frequently, so that the reference discharge pressure waveform can be obtained frequently. The frequency of implementation varies depending on the laboratory, but it is implemented monthly, for example. The second point is that since this process is performed in daily equipment operation, no special work is required for the equipment user to acquire the reference discharge pressure waveform. Further, as described above, since the assay calibration is performed for all the inspection items, there is an advantage that a reference discharge pressure waveform corresponding to all the dispensing amounts applied by the apparatus can be obtained. Furthermore, one of the major advantages is that the sample used in the assay calibration generally has a viscosity suitable for the device and is therefore very suitable as a reference fluid.

In addition, instead of assay calibration, acquisition of a reference discharge pressure waveform at the time of performing quality control measurement can also eliminate the influence of the difference in the inspection date. The frequency varies depending on the laboratory, but since it is carried out on a daily basis, for example, it can be expected that the reference discharge pressure waveform will be obtained diligently. Furthermore, as with assay calibration, it does not require any special work for the device user because it is performed in daily device operation. The reference fluid in this case is a quality control sample.

It is also possible to measure the reference discharge pressure waveform in the preparatory step before the start of analysis and in the steps before and after sample dispensing. By adopting this method, all the factors mentioned so far can be removed. Examples of the reference fluid include purified water and air (air suction).

FIG. 12 shows the vicinity of the dispensing probe when a container for receiving the reference fluid is installed on the sample dispensing unit when a liquid sample such as purified water is used as the reference fluid, and the sample is dispensed from there at any time. It is a figure which shows.

For example, there is a method of installing a container 1902 for receiving the reference fluid and a container 1903 as a discharge destination when dispensing the reference fluid on the rotation orbit of the sample probe 1901. A reference discharge pressure waveform can be obtained when a reference fluid such as purified water is dispensed from the container 1902 in the preparatory operation step before the start of analysis and the steps before and after sample dispensing. It is not always necessary to install the container 1903 as the discharge destination of the reference fluid, and for example, the container 1902 may be discharged as it is.

According to the present invention, by paying attention to the pressure difference or pressure ratio of the pressure in the dispensing flow path at the time of liquid discharge from the reference discharge pressure waveform, it is possible to accurately detect an abnormality due to bubble suction at the time of liquid suction. .. In particular, even when the suction amount is very small, highly accurate detection is possible, so that it is possible to prevent reporting the above measurement result due to an abnormality in dispensing to the operator.

In addition, various known correction processes may be applied to the obtained waveform. The correction processing includes, for example, offset deviation correction, peak rise timing deviation correction, smoothing processing, and period / amplitude deviation correction. By performing these correction processes, it is possible to remove individual differences in hardware, influences of the surrounding environment such as the installation environment of the device, daily differences, etc., and accurately detect the presence or absence of bubbles.

Further, in the present invention, the abnormality determination at the time of sample suction has been described as an example, but it is also possible to target a liquid other than the sample. For example, it is also possible to apply the present invention to an abnormality determination at the time of suction of a reagent, a buffer solution, a diluent, a cleaning solution, or the like.

Furthermore, if a container that receives the reference fluid is placed on the movement path of the probe, the timing of acquiring the reference discharge pressure waveform can be appropriately selected to suppress the pressure waveform from fluctuating due to various causes, and the detection of the present invention can be performed. You can maximize the performance.

101: Automatic analyzer, 102: Specimen rack, 103: Rack transfer line, 104: Reagent cold storage unit, 105: Incubator disk, 106: Sample dispensing mechanism (sample dispensing mechanism), 107: Reagent dispensing mechanism, 108: Consumables transport unit, 109: detector unit, 110: sample container (sample container), 111: reagent container, 112: reagent disk cover, 113: reaction vessel, 114: reaction vessel arrangement unit, 115: dispensing chip, 116 : Consumables storage container 117: Storage container holding unit, 118: Spare storage unit 119: Transport mechanism, 120: Chip mounting position, 121: Discard hole, 122: Control unit, 123: Operation unit, 124: Control device, 125: Storage device 201: Chip, 202: Specimen probe, 203: Flow path, 204: Syringe, 204a: Cylinder, 204b: Plunger, 205: Syringe driving means, 206: Specimen probe driving means, 207: Control unit, 208: Container, 209: Sample, 210: Water supply pump, 211: Water supply tank, 212: Washing water, 213: Electromagnetic valve, 214: Pressure sensor, 215: Branch block, 216: Signal amplifier, 217: A / D converter, 218 : Judgment unit, 219: Sampling unit, 220: Storage unit, 221: Comparison unit 401: Liquid sample, 402: Bubble, 403: Chip

Claims (7)

A probe that performs a dispensing operation including a suction process and a discharge process for a liquid,
A syringe that generates pressure fluctuations for dispensing liquid with the probe,
A flow path connecting the probe and the syringe,
A pressure sensor that measures the pressure fluctuation in the flow path during liquid dispensing, and
A storage unit that stores time-series pressure fluctuations when the reference fluid is discharged as a reference discharge pressure waveform,
And the value of the difference or the ratio of the pressure waveform at the time of discharging a liquid to be determined and the reference discharge pressure waveform, the relationship between the predetermined range, a determination unit to whether there is an abnormality in the suction step of the liquid body , With
The storage unit stores the relationship between the timing outside the predetermined range and the amount of air mixed in the liquid for each preset dispensing amount.
The determination unit is an automatic analyzer having a function of estimating the amount of air mixed in from a timing outside the predetermined range. In the automatic analyzer according to claim 1,
The storage unit is an automatic analyzer that stores the reference discharge pressure waveform and the predetermined range for each set dispensing amount. In the automatic analyzer according to claim 1,
The determination unit is an automatic analyzer having a function of estimating the cause of an abnormality based on the estimated amount of air sucked in the suction step. In the automatic analyzer according to claim 1,
The reference discharge pressure waveform is obtained at the time of discharging the calibrator measured at the time of performing the assay calibration, the pressure waveform obtained at the time of discharging the quality controlled sample measured at the time of performing the quality control measurement, and the time of discharging the purified water. An automatic analyzer that is either a pressure waveform or a pressure waveform obtained when air is discharged. In the automatic analyzer according to claim 1,
The reference discharge pressure waveform is acquired at any time of shipment of the automatic analyzer, installation of the automatic analyzer, preparatory operation before the start of analysis, or before and after suction and discharge of the liquid . Automatic analyzer. In the automatic analyzer according to claim 1,
An automatic analyzer comprising a container for receiving purified water as the reference fluid on the moving path of the probe. In the automatic analyzer according to claim 1,
When air is used as the reference fluid, the determination unit uses air suction when the difference or ratio between the pressure waveform when the liquid is discharged and the reference discharge pressure waveform does not deviate from the predetermined range during the discharge process. It is determined that there is, and after the discharge operation of the syringe is completed after the deviation from the predetermined range, if the suction is within the predetermined range again, it is determined that the suction is normal. An automatic analyzer that determines that the gas is mixed.

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